High throughput genotyping of SNPs promises to revolutionize our understanding of genetic variation and the ability to relate genetic variation to phenotypic variation, including disease for 3 reasons: (1) the number of SNPs which are potentially available -more than 300,000 across the human genome; (2)SNPs represent the majority of sequence variants which alter the structure and expression of gene products; (3) these variants are amenable to analysis by automated methods. We have implemented high throughput genotyping of SNPs using TaqMan type primer/probe methodology in which each allele in a biallelic polymorphism generates a different fluorescent signal which can be quantitated immediately following PCR [on an end-point multiwell fluorescent detector - the Cytofluor 4000] or even during PCR [using the PE 7700 which permits quantitation during each PCR cycle]. A critical issue is the ability to develop algorithms for automated allele calling. Using a set of readily genotyped and more problematically genotyped SNPs, we have made an advance over the available technology for automated genotype calling. We have used a K- means clustering algorithm that evaluates the ratio of the two fluuorescent allele signals to make accurate genotype calls on data that would have needed manual evaluation. - automated genotyping, single nucleotide polymorphisms